Soluble Epoxide Hydrolase Inhibition and Insulin Resistance

NCT03486223 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 1704685R01DK117875
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test how soluble epoxide hydrolase (sEH) inhibition with GSK2256294 affects tissue sEH activity and insulin sensitivity.

Conditions

Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; PreDiabetes; Obesity

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity

  Insulin sensitivity determined by Hyperinsulinemic-Euglycemic Clamp as the glucose infusion rate (GIR) per fat-free-mass (FFM) during high dose insulin infusion

  Day 7

Secondary Outcomes (4)

• Forearm Blood Flow (FBF)

  Day 7

• Insulin Signaling in Tissue

  Day 7

• Blood Pressure

  Day 7

• Renal Plasma Flow (RPF)

  Day 7

Other Outcomes (6)

• Soluble Epoxide Hydrolase Activity

  Day 7

• Plasma Total Epoxyeicosatrienoic Acids (EETs)

  Day 7

• Plasma IL-6

  Day 7

Study Arms (2)

Placebo then GSK2256294

EXPERIMENTAL

Subjects will receive placebo oral capsule daily by mouth for 7 days, then seven week washout and then GSK2256294 daily by mouth for 7 days.

Drug: GSK2256294; Drug: Placebo oral capsule

GSK2256294 then Placebo

EXPERIMENTAL

Subjects will receive GSK2256294 daily by mouth for 7 days, then seven week washout and then placebo oral capsule daily by mouth for 7 days.

Drug: GSK2256294; Drug: Placebo oral capsule

Interventions

GSK2256294 DRUG

Drug will be taken daily by mouth for 7 days.

Also known as: GSK2256294 10mg oral capsule

GSK2256294 then Placebo; Placebo then GSK2256294

Placebo oral capsule DRUG

Placebo will be taken daily by mouth for 7 days.

Also known as: Placebo

GSK2256294 then Placebo; Placebo then GSK2256294

Eligibility Criteria

• Age: 21 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women,
• Age 21 to 50 years, and
• Pre-diabetes as defined by
• Fasting plasma glucose 100-125 mg/dL, or
• Two-hour plasma glucose 140-199 mg/dL, or
• HbA1c 5.7-6.4%
• BMI ≥ 30 kg/m2, inclusive
• For female subjects, the following conditions must be met:
• Postmenopausal status for at least one year, or
• Status-post surgical sterilization, or
• If of childbearing potential, utilization of adequate birth control and willingness to undergo serum β-hcg testing prior to drug treatment and on every study day.

You may not qualify if:

• Diabetes type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, a HbA1c \>6.4%, or the use of anti-diabetic medication
• Subjects who have participated in a weight-reduction program during the last six month or whose weight has increased or decreased more than two kg over the preceding six months
• Resistant hypertension, defined as hypertension requiring the administration of more than three anti-hypertensive agents including a diuretic to achieve control
• Use of spironolactone
• Pregnancy or breast-feeding
• Any history of smoking
• Any history of cancer including skin cancer, any history of a precancerous lesion, abnormal PSA, or lack of screening adherent to American Cancer Society Guidelines for the Early Detection of Cancer
• Cardiovascular disease such as myocardial infarction within six months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep-vein thrombosis, pulmonary embolism, second- or third-degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy
• Abnormal corrected QT interval on screening ECG (QTc).
• Treatment with anticoagulants
• History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
• History or presence of immunological or hematological disorders
• Diagnosis of asthma requiring regular inhaler use
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>3.0 x upper limit of normal range)

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (4)

• Luther JM, Brown NJ. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat. 2016 Sep;125:2-7. doi: 10.1016/j.prostaglandins.2016.07.010. Epub 2016 Jul 19.

  PMID: 27448715 BACKGROUND

• Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther JM. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017 Jun;60(6):1066-1075. doi: 10.1007/s00125-017-4260-0. Epub 2017 Mar 28.

  PMID: 28352940 BACKGROUND

• Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

  PMID: 25173047 BACKGROUND

• Luther JM, Ray J, Wei D, Koethe JR, Hannah L, DeMatteo A, Manning R, Terker AS, Peng D, Nian H, Yu C, Mashayekhi M, Gamboa J, Brown NJ. GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans. Hypertension. 2021 Sep;78(4):1092-1102. doi: 10.1161/HYPERTENSIONAHA.121.17659. Epub 2021 Aug 30.

  PMID: 34455816 RESULT

MeSH Terms

Conditions

Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Prediabetic State; Obesity

Interventions

N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Enrollment was not sufficient for subgroup analysis for race and gender, due to drug expiration.

Results Point of Contact

• Title: Dr. James M Luther
• Organization: Vanderbilt University Medical Center

james.luther@vumc.org

6153223353

Study Officials

• James M Luther, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

• Nancy J Brown, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Arms 1/2 are placebo controlled and blinded to investigator and participant
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: Arm 1 and 2 are crossover arms

Study Record Dates

• First Submitted: March 27, 2018
• First Posted: April 3, 2018
• Study Start: May 17, 2018
• Primary Completion: November 18, 2021
• Study Completion: November 18, 2021
• Last Updated: March 23, 2023
• Results First Posted: March 23, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)